6
Investigation and Management of Malignant Anal-Canal Tumours
Najjia N. Mahmoud and Robert D. Madoff
1. Introduction
Tumours of the anal margin and canal are a rare but histologically diverse group of neoplasms. In the United States, anal-canal carcinoma accounts for 1.5% of digestive system cancers, with an estimated 3400 new cases diagnosed each year [1]. Despite its infrequency, insights into anal-cancer biology over the past 30 years have radically altered its management. In the past, chronic conditions such as haemorrhoids, fistulas, and fissures were thought to cause anal cancer. This belief has been replaced with the knowl- edge that human papilloma viruses and chronic immunosuppression play critical roles. Thirty years ago, abdominoperineal resection was the standard treatment for patients with anal cancer. Today, chemoradiation has rede- fined therapy, allowing many patients to retain gastrointestinal continuity with lower morbidity. This chapter overviews the causes, diagnosis, and treatment of anal-canal carcinoma in the context of the rapid changes in this field in the past 30 years.
2. Anatomic Features
Traditionally, the anus is divided into the mucosa-lined anal canal and the more distal epidermis-covered anal margin. Confusion in the literature over precise anatomic localisation of tumours has resulted from reporting errors and differences of opinion among clinicians and researchers. These incon- sistencies have made comparisons of studies difficult and may confound outcomes. The World Health Organization (WHO) recently defined the anal canal and margin in histologic and anatomic terms, in keeping with the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system; it is this definition that most clinicians and researchers have now agreed on [2]. By this definition, the anal canal extends from the rectum to the perianal skin and is lined by the mucosa overlying the internal sphincter. Importantly, this definition
115
includes the anal transition zone (ATZ) epithelium and the non–hair- bearing and non–sweat-gland bearing squamous mucosa extending distally to its junction with skin. Anal margin refers to the junction of the skin and the squamous mucosa of the anal canal. Anal-margin tumours are, for this reason, staged according to the system used for skin cancers.
Histologically, the mucosa of the anal canal is divided into three zones.
The upper zone is located above the ATZ and comprises colorectal-type mucosa. The ATZ extends variably above and below the dentate line for about 1–2 centimeters vertically, in fingerlike projections that vary in length both between subjects and within the same individual [3]. Fenger, in a classic study of the anatomy and histology of the anal canal, defined the extent of the ATZ and its relationship to the dentate line with alcian blue—a stain that renders mucin-rich columnar epithelium dark blue, mucin-poor transi- tional epithelium light blue, and squamous epithelium colorless. According to Fenger, the dentate line ranged from 5 to 19 mm above the lower end of the anal canal. The ATZ was generally located above the dentate line, but in a number of canals, the borders of this zone extended 3 to 6 mm below it [4].
Tumours arising distal to the dentate line are usually keratinising squa- mous-cell carcinomas, whereas those arising in the ATZ and above are typically nonkeratinising. Because of the complex gross and histologic anatomy of this region, classification of anal neoplasms has been a source of confusion and inconsistency. Most pathologists use the World Health Organization (WHO) classification. According to the WHO classification, anal canal lesions consist of squamous-cell (cloacogenic) variants, including keratinising, nonkeratinising, and basaloid tumours [2]. Anal-canal lesions may also include adenocarcinoma, and other more rare lesions such as carcinoid, anal lymphoma, and melanoma. Anal-margin tumours include squamous-cell carcinoma, giant condyloma (verrucous carcinoma), basal- cell carcinoma, and variants of anal intraepithelial neoplasia sometimes termed Bowen’s disease. Paget’s disease refers to adenocarcinoma-in-situ.
For more detailed discussion of these subtypes, see the Histology section.
The dentate line provides an anatomic reference point for lymphatic drainage of the anal canal and margin. Above the dentate line, drainage is primarily via the superior rectal lymphatics to the inferior mesenteric nodes and laterally along the middle and inferior rectal vessels [5,6]. Lesions distal to the line drain to the inguinal and femoral lymphatics (Figure 6.1).
Tumours in the ATZ may follow both lymphatic routes. Patients with unex- plained inguinal lymphadenopathy should undergo a careful examination of the anal canal.
3. Presentation and Physical Findings
By far, the most common presenting symptom of anal cancer is rectal bleed- ing, which occurs in 45% of patients. Another 30% have pain or the sensa- tion of a rectal mass, whereas 20% have no symptoms at all [7,8]. Initially,
many patients may have symptoms of persistent bleeding and itching. In one series, more than 50% of the cases documented were diagnosed more than 2 years after the onset of symptoms [9]. Prompt diagnosis and treat- ment of anal-canal and -margin cancers can be difficult. Stearns and Quan reported that one third of such cancers in their series were initially misdi- agnosed as benign inflammatory disease [10]. More advanced cases involv- ing the anal sphincter can cause tenesmus and incontinence. A common problem arises when haemorrhoid specimens sent for routine histopathol- ogy are found to contain areas of cellular atypia, high- or low-grade intra- epithelial neoplasia, or invasive cancer; in such individuals, treatment and follow up are controversial.
4. Risk Factors
In the past, the commonly held notion was that benign anorectal conditions, such as haemorrhoids, fissures, and fistulas, predispose to the development of squamous-cell carcinoma (SCC). The cause or common mechanism was presumed to be prolonged exposure of the anal-canal epithelium and margin to chronic inflammatory conditions. Similarly, patients with inflam- matory bowel disease were believed, on this basis, to be at increased risk, particularly when anal fistulas were present. In 1994, Frisch examined this issue in a large population and did not find a causal relationship between 6. Investigation and Management of Malignant Anal-Canal Tumours 117
To inguinal nodes Inferior
rectal artery Middle rectal artery Superior rectal artery
A Interior B
mesenteric artery
Common iliac artery
Figure 6.1. Lymphatic drainage routes of the rectum and anus. (Reprinted with permission from Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery of the Colon, Rectum, and Anus. St. Louis, MO: Quality Medical Publishing, Inc, 1992:30.)
benign anorectal conditions and anal cancer, up to 13 years after resolution of the benign condition [11]. In a similar large population study, Frisch identified 9602 Danish patients with a diagnosis of either Crohn’s disease or ulcerative colitis (mean follow up, 10 years). Only 2 patients developed anal squamous-cell carcinoma in this time, both of whom had had Crohn’s disease or ulcerative colitis more than 15 years. Frisch concluded that although long-term sufferers of irritable bowel disorders may be at slightly increased risk of anal SCC, short- and mid-term risk is not significantly dif- ferent from that of the general population [12].
4.1. Lessons from Cervical Cancer
In contrast, striking evidence links human papilloma virus (HPV) infec- tion with the development of anal SCC and anal intraepithelial neoplasia (AIN). HPV is a double-stranded DNA tumour virus with a predilection for mucoepithelial tissues. More than 100 types of HPV have been identi- fied overall, but only 30 types have been found in conjunction with either anal SCC or AIN. Furthermore, HPV 6 and 11 are nononcogenic—they are associated with lesions such as low-grade anal squamous intraepithelial lesions (LSIL) and condyloma acuminatum. Oncogenic or high-risk types 16 and 18 are associated with invasive anogenital cancers and lesions with the potential to progress to invasive cancer, such as high-grade squamous intraepithelial lesions (HSIL) [13].
In the general population, the incidence of anal cancer has been observed to have a female predilection, occurring in women at almost twice the rate as men. However, for more than 60 years, an increased risk of anal cancer in homosexual men has been noted [14]. The identification of a high-risk population with numerous sexual partners and other venereal diseases made an infectious agent seem likely. This likelihood is strengthened by recent studies demonstrating an increase in anal-canal cancer in hetero- sexual men and in women with numerous partners of the opposite sex; both these subgroups have a heavy burden of venereal disease. Current estimates show that the risk of anal cancer in American homosexual men practicing anal-receptive sex may be even higher than the risk of cervical cancer in American women [15]. The incidence of cervical cancer in the United States is now about 8 per 100,000. The incidence of anal cancer, in both men and women in the general population, is about one tenth that figure. The estimated incidence in men with a history of receptive anal intercourse is about 35 per 100,000—a figure on par with the incidence of cervical cancer in women before screening programs were instituted [13]. In the United States, according to the Surveillance, Epidemiology, and End Results (SEER) program, the relative risk of developing anal cancer is 4.6 in women who had a prior diagnosis of cervical cancer [16].
Interest in the viral pathogenesis of anal intraepithelial lesions and inva- sive anal cancer began with the investigation of the HIV epidemic. Most
current studies focus on data collected before the advent of highly active anti-retroviral therapy (HAART) in HIV-positive homosexual men.
Again, cervical cancer provides an excellent model for the study of anal cancer. Both types occupy anogenital mucoepithelium in an epithelial transformation zone, both are frequently associated with HPV, and both are recognized to have a noninvasive dysplastic precursor lesion. Most of the hypotheses about the natural history and pathogenesis of anal cancer are directly extrapolated from the well-documented example of cervical cancer. Prospective data on the biological ramifications of HPV infection and on the HSIL and LSIL precursor lesions in the HIV-positive as well as HIV-negative subpopulations are just now being gathered.
No published studies to date have documented the progression of HSIL to anal cancer; however, it seems likely that—with time and adequate follow up, in light of the cervical cancer literature—this connection can be established. Obviously, investigation is hampered by low case numbers in the non-HIV subpopulation and by short follow-up times among study patients in the HIV-positive population (because of the morbidity of their underlying disease). It is not known how HAART will affect the natural history of HSIL and LSIL. Similarly, it is unclear how close follow- up with concomitant clinical intervention might change outcome data [13,17–19].
4.2. HIV Infection
Emerging data from ongoing studies show that 93% of HIV-positive homosexual men and 61% of HIV-negative homosexual men have HPV DNA as detected by PCR sampling. HPV 16 was the most prevalent viral serotype, but 73% of HIV-positive men had multiple types compared with 23% of HIV-negative men [20]. In one recent study, the relative risk of developing ASIL increased with decreasing CD4 counts. Other investiga- tors, following a San Francisco cohort of homosexual men, found that 49%
of the 277 HIV-positive men and 17% of the 221 HIV-negative men devel- oped HSIL over a 4-year period [13]. Risk factors for progression to HSIL include infection with multiple HPV types, high-level infection with onco- genic HPV types, and chronic anal infection. A limited number of small studies have documented the effects of HAART on the natural history of anal-canal cancer. Evidence from these studies suggests that those patients progressing to anal cancer had lower CD4 counts [13,17,21,22]. In these same studies, those patients with high CD4 counts had the highest rate of HSIL regression to LSIL. Clearly, it is still too early to make definitive state- ments regarding the impact of HAART on the natural history and pro- gression of ASIL to invasive cancer; however, trends suggest that patients on chronic immunosuppression and HAART nonresponders may have a greater risk of developing invasive precursors. Longer follow up is needed to establish this definitively.
6. Investigation and Management of Malignant Anal-Canal Tumours 119
4.3. Smoking
Several case-control studies have demonstrated that smoking increases the risk of anal cancer by a factor of 2 to 5, independently of sexual practices [16,23]. The antiestrogenic effect of smoking is speculated to potentiate the neoplastic effects of oncogenic HPV serotypes [24]. Conversely, lung cancer is more than twice as frequent in those with anal cancer as in the general population.
4.4. Chronic Immunosuppression
An increased risk of persistent HPV infection is correlated with an increased likelihood of anal cancer. Patients on long-term corticosteroid immunosuppression do not have an increased risk of anal-canal cancer, but they do harbor persistent HPV infection [29].
5. Diagnosis
The diagnosis of anal-margin and -canal tumours can be delayed when mistaken for benign conditions. Malignancy must be considered when treatment for anal dermatitis fails, or when pruritus ani proves refractory to medical therapy. Obvious firm masses and bleeding, friable, ulcerated lesions require prompt biopsy. A thorough physical examination includes specific attention to the anogenital region and the inguinal lymph nodes.
Computed tomography (CT) of the abdomen and pelvis and a chest X-ray are the standard extent-of-disease evaluation of anal cancer. Other imaging studies that may help determine depth of invasion include magnetic reso- nance imaging (MRI) and endoanal ultrasound (EAUS). There is currently no specific EAUS protocol for the diagnosis or posttreatment follow up of patients. However, at our institution, we use this technique for all newly diagnosed anal-canal cancers to quantify the size of the lesion, to determine the extent of sphincter involvement, and to detect the presence of regional lymph nodes (although the significance of the latter finding remains uncer- tain). EAUS is also used in the follow up of treated patients to detect early recurrences (Figure 6.2) [25,26].
The role of total colonic evaluation for patients diagnosed with anal- canal carcinoma has been debated. Current evidence seems to support the view that squamous-cell carcinoma variants do not represent an increased risk for synchronous colonic adenomas or adenocarcinomas [27]. However, full colonoscopic evaluation remains a part of many clinicians’ practice.
Many patients evaluated for anal-cancer require colonic screening for routine preventive reasons.
6. Classification and Terminology
6.1. Location
Anal-canal tumours are defined by their location and histologic grade. The most commonly accepted anatomic description of the anal canal has been put forth by the WHO and agreed on by the AJCC/UICC. The canal extends from the rectum to the perianal skin and is lined by the mucous membrane overlying the internal sphincter (Figure 6.3). Therefore, the anal 6. Investigation and Management of Malignant Anal-Canal Tumours 121
A B
Figure 6.2. (A) Pre-chemoradiation therapy. (B) Eighteen months post- chemoradiation therapy. (Ultrasound images courtesy Dr. Julio Garcia-Aguilar.)
Column of Morgagni Dentate line Anal crypt Anal gland Anoderm Transitional
Anal canal zone
Figure 6.3. The anal canal, ATZ, and anal margin. (Reprinted with permission from Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery of the Colon, Rectum, and Anus. St. Louis, MO: Quality Medical Publishing, Inc, 1992:12.)
canal encompasses the ATZ epithelium and the non–hair-bearing and non–
sweat-gland-bearing squamous mucosa extending distally to its junction with skin. Anal margin refers to the junction of the skin and the squamous mucosa of the anal canal. Anal-margin tumours are, for this reason, staged according to the TNM system used for skin cancers.
6.2. Histology
Before the WHO classification proposed by Jass and Sobin in 1989, anal- canal tumour location and histologic information was highly variable and confusing [28]. Terminology was nonstandard and even now makes mean- ingful retrospective meta-analysis of the literature quite difficult. Although the majority of anal-canal tumours are variants of squamous-cell carcinoma, the anal canal and margin contain numerous examples of mixed histologic cell types that have spawned various histologic designations. For example, although the WHO classification designates all anal-canal squamous- cell variants as cloacogenic, other systems regard only those variants with basaloid features (that is, containing small palisading cells that histo- logically resemble basal-cell carcinoma) as cloacogenic. Other variants are designated mucoepidermoid, referring to the histologic admixture of squa- mous cells and mucus-producing cells. In the anal canal, about 50% of squamous-cell tumours show a degree of keratinisation; in the anal margin, about 80%. All of these cell types are thought to arise from the transitional epithelial tissue that constitutes the dentate line [6]. Fortunately, neither treatment nor prognosis seems to depend on these rather arbitrary desig- nations (Table 6.1).
7. Treatment
7.1. Background
Nearly 80% of anal-canal tumours are either SCC or histologic variants of SCC such as epidermoid, transitional cell, or basaloid [29]. All of these variants arise in the anal transition zone. As mentioned before, variable terminology has led to confusion in the literature; however, there is no difference in treatment or outcome among these tumours [2]. Another 10%
of anal-canal tumours are adenocarcinomas; the remaining 10% are mainly melanomas, carcinoids, and leiomyosarcomas.
The treatment of anal-canal carcinoma has a dynamic recent history, having undergone major changes within the past 3 decades. Before 1974, the standard of care was either wide local excision (for tumours judged to be superficial), or abdominoperineal resection (APR) (for tumours invad- ing the external sphincter). Outcomes were poor, with overall survival rate after APR ranging from 30% to 70% depending on tumour grade, stage,
Table 6.1. WHO classification of carcinoma of the anus.
Histologic Classification Anal Canal
Malignant epithelial tumours
Squamous-cell (cloacogenic) carcinoma Large-cell keratinising
Large-cell nonkeratinising (transitional) Basaloid
Adenocarcinoma Rectal type Of anal gland
Within anorectal fistula
Small-cell carcinoma (designated as histologic grade 3) Undifferentiated (designated as histologic grade 4) Anal Margin
Malignant epithelial tumours Squamous-cell carcinoma
Giant condyloma (verrucous carcinoma)*
Basal-cell carcinoma*
Others
Bowen’s disease (squamous intraepithelial neoplasia)*
Paget’s disease (adeno intraepithelial neoplasia)
*These types are not usually graded, although Bowen’s disease corresponds to high-grade squamous intraepithelial lesions (HSIL) and squamous carcinoma-in-situ (CIS).
Histologic Grade
Histologic grade for anal squamous-cell cancers are listed. In tumours with mixed grades, the most poorly differentiated is recorded.
Grade X Grade cannot be assessed Grade 1 Well differentiated Grade 2 Moderately differentiated Grade 3 Poorly differentiated Grade 4 Undifferentiated Regional Lymph Nodes
In the TNM system, regional lymph nodes in anal-canal or -margin cancer consist of the perirectal, mesorectal, internal iliac (hypogastric), and superficial and deep inguinal nodes.
All other nodal groups are regarded as metastatic disease and given an M designation.
TNM Staging
TNM staging (AJCC/UICC designations) for anal-canal carcinoma is shown below.
Anal-margin tumours are staged according to skin cancer classifications, and melanomas are grouped separately as well. T refers to primary tumour size and local extension. N
designates locoregional nodal involvement, and M implies distant spread.
Primary Tumour (T)
TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ
T1 Tumour <2 cm in greatest dimension
T2 Tumour >2 cm but not >5 cm in greatest dimension T3 Tumour >5 cm in greatest dimension
T4 Tumour of any size invades adjacent organ(s), e.g., vagina, urethra, bladder (involvement of muscle alone is not classified as T4)
and size [30–32]. In a series from Singh et al. at Roswell Park Memorial Institute, the local recurrence rate after wide resection or APR was 25% to 35% for all stages; for tumours invading through the submucosa, 100% [8].
Perineal or pelvic recurrence occurs in 50% to 70% of patients undergoing APR; only 10% die of distant disseminated disease [9].
7.2. Local Excision
Although chemotherapy and radiation result in higher disease-free survival rates, local excision still has a role in anal-canal carcinoma. Local resection with curative intent should be restricted to small (less than 1 cm), well- differentiated tumours confined to the submucosa. A retrospective analy- sis of local excision and survival rates at the University of Minnesota Table 6.1. Continued
The TNM system allows for the classification of nonsurgically treated tumours whether by chemoradiation, chemotherapy, radiation alone, or polypectomy. The R designates residual disease.
RX Presence of residual tumour cannot be assessed R0 No residual tumour
R1 Microscopic residual tumour R2 Macroscopic residual tumour Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in perirectal lymph nodes
N2 Metastasis in unilateral internal iliac and/or inguinal lymph nodes
N3 Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes
Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed M0 No distant metastasis
M1 Distant metastasis Stage Groupings
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage IIIA T1 N1 M0
T2 N1 M0
T3 N1 M0
T4 N0 M0
Stage IIIB T4 N1 M0
Any T N2 M0
Any T N3 M0
Stage IV Any T Any N M1
revealed a direct correlation between survival and tumour size. For tumours greater than 2.5 cm, 5-year survival rates were 60% [29]. For those that were less than 1 cm, survival rates were much higher. Corman and Haggitt reported a similar experience: all tumours confined to the submucosa were cured by local excision or APR; those that extended beyond the submucosa eventually recurred [33]. Longo recorded a 62% failure rate in stage I–III tumours that were treated solely by local excision: all stage II and III tumours recurred [34]. Tumour accessibility, full-thickness excision, and 1-cm margins seem imperative for local resection.
7.3. Preoperative Chemotherapy and Radiation
The treatment of anal-canal carcinoma has changed radically with the advent of chemoradiation protocols in the late 1970s. In 1974, Norman Nigro, working at Wayne State University School of Medicine, defined a treatment protocol involving the administration of 5-FU, mitomycin-C, and preoperative radiation to shrink the tumours. The radiation (30 Gy total) was given in 15 sessions over a 3-week period. The 5-FU was administered at a dose of 1000 mg/m2/d for 4 days, starting on the first day of radiation therapy, as a continuous infusion; it was then repeated on days 29 through 32. Mitomycin-C (15 mg/m2) was administered as a single dose on day 1 of treatment [35]. Although the pretreatment tumour size averaged 5 cm, pathologic examination yielded residual tumour in only 7 of the 45 patients studied. All 7 patients with residual tumour died of disseminated disease [35]. Follow up was under 5 years for many of the patients, but their 89%
disease-free survival rate fueled intense interest in preoperative chemora- diation and spawned a number of studies with similar multimodality regi- mens. Some of these studies used radiation, alone or with other therapies, followed by surgical excision to assess pathologic response.
A number of radiation delivery techniques have been described in the literature. The 2-field anterior–posterior (AP–PA) technique and the 3-field posterior–anterior technique are most commonly used. Typically, a dose of 1.8 Gy/d 5 times per week results in a standard total dose of 45 Gy in 5 weeks. If N1 disease is detected, the fields can be flared to include the inguinal nodes [4,7]. Enker at Memorial Sloan-Kettering Hospital reported that 59% of patients treated with both chemotherapy and radiation were downstaged to pT0 [36]. All of these patients had undergone APR or wide local excision after radiation treatment.
Most multimodality studies since Nigro’s 1974 publication have used 5-FU and mitomycin-C as the chemotherapeutic agents. However, several have made dose and infusion modifications, and nearly all have varied the radiation dose upward. Maximal doses have been in the range of 50 Gy. Because of such variability among similar therapies, meta-analy- sis is difficult. However, direct comparison between studies is useful (Table 6.2).
6. Investigation and Management of Malignant Anal-Canal Tumours 125
In 1996, the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) published the largest prospective randomised study of chemotherapy and radiation versus radiation alone. The trial enrolled 585 patients, assigning them to either combined therapy or radiation alone, and then assessed them at 6 weeks. Poor responders were then offered APR and good responders were given a boost of radiotherapy and reassessed.
Those patients receiving radiation alone had a local failure rate of 59%, whereas those on combined therapy had a 36% local failure rate (mean follow up, 42 months) [37]. The early morbidity of combined therapy was higher than with radiation alone; in fact, 2 patients died of sepsis. However, the late morbidity rate was the same. With combined therapy, the local failure rate was halved, as was the number of patients requiring salvage surgery. In all, of 174 patients on combined therapy (with a boost of radio- therapy), 29 required salvage APR; of 188 on radiation alone, 72 required salvage APR. Although the local failure rate for radiation alone was higher, overall survival between the groups was the same [37].
Also in 1996, Flam et al. further explored the role of 5-FU and mito- mycin-C as radiation-sensitising agents in a phase III prospective ran- domised RTOG/ECOG trial [38]. A total of 310 patients were randomised to receive either radiation with 5-FU or radiation with both 5-FU and mitomycin-C. Flam concluded that, although the addition of mitomycin-C produced slightly greater toxicity, at 4 years the disease-free survival was higher (73% vs 51%, P = .0003). However, as in the UKCCCR trial, improved overall survival rates could not be demonstrated [38].
In 1997, the third large randomised trial comparing combined therapy with radiation alone for of anal-canal carcinoma was reported by the Euro- pean Organisation for Research and Treatment of Cancer (EORTC); this phase III trial involved 110 patients [39]. The addition of chemotherapy (5-FU and mitomycin-C) resulted in a complete response rate of 54% with radiation alone and 80% with combined therapy. The actuarial 5-year locoregional control rate improved by 18%; colostomy-free survival, by 32%. As in the UKCCCR study, however, no definite overall survival Table 6.2. Results of combined chemoradiation.
Author, Patients Type of Dose Complete Follow
Year (n) Chemotherapy (Gy) Regression (%) Up (m)
Cummings et al., 1984 16 5-FU MTC 50 94 48–84
Cummings et al., 1984 14 5-FU MTC 25 + 25 100 30–48
Sischy, 1985 33 5-FU MTC 55–65 91 12–108
Cummings, 1987 18 5-FU MTC 24 + 24 89 6–30
Meeker et al., 1986 19 5-FU MTC 30 87 30 (median)
Flam et al., 1987 30 5-FU MTC 41–50 87 9–76
Nigro, 1987 104 5-FU MTC 30 93 24–132
Table modified from Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery of the Colon, Rectum, and Anus. St. Louis, MO: Quality Medical Publishing, Inc, 1992:412.
advantage could be demonstrated. Most patients whose cancer recurred did not respond to local excision, yet the authors observed an advantage to adding chemotherapy to radiation in larger tumours: the event-free survival rate was lower, with similar toxicities [39] (Table 6.3).
7.4. Inguinal Lymphadenectomy
Before the advent of chemoradiation, radical inguinal lymphadenectomy was advocated as a useful adjunct to primary resection. Recent evidence reveals an extremely high morbidity associated with it, with little apparent benefit in preventing local or distant recurrence [7,10,33]. Current recom- mendations focus on the use of therapeutic inguinal lymphadenectomy to reduce the complications and discomfort of rapidly growing groin tumours.
The inguinal area is frequently included in the radiation portal when deliv- ering adjuvant therapy; however, this technique is not complication- free. Fibrosis and inflammation can result in debilitating lymphedema that can be permanent, thus requiring the judicious use of fitted graded- compression garments, leg elevation, or both.
8. Recurrent Disease and Surgical Salvage
Anal-canal carcinoma metastasises rarely (in less than 10% of patients) and late. The most common sites of distant spread are the liver and lungs.
Patients with recurrence tend to die of locoregional complications, includ- ing ureteral obstruction, perineal sepsis and necrosis, bowel obstruction, and venous thrombosis. The goal of early detection of perineal posttreatment recurrences is to prevent lymphatic disease spread. In a retrospective analy- sis of salvage therapy for recurrent disease after chemoradiation, Allal et 6. Investigation and Management of Malignant Anal-Canal Tumours 127
Table 6.3. Five-year local recurrence rates and disease-free survival rates in prospective studies.
Author, Year Patients Radiation Median 5-year Local 5-year, Disease- (n) Dose (rads) Follow Up Recurrence free Survival
(m) Rate (%) Rate (%)
UKCCCR, 1996a 290 45 42 59 60
UKCCCR, 1996 295 45 42 36 39
EORTC, 1997a 52 45 42 46 n/a
EORTC, 1997 51 45 42 20 n/a
Flam et al., 1996a 145 45–50.4 36 34 51b
(5-FU)
Flam et al., 1996a 146 45–50.4 36 16 73b
(5-FU+ MMC)
aCombined chemotherapy with radiation administered. Flam et al. prospectively compared radiation with 5-FU vs 5-FU+mitomycin C (MMC).
b4-year actuarial disease-free survival rates.
al. found that patients who underwent APR had a 53% actuarial 5-year sur- vival rate; those who didn’t receive additional treatment, 28% [40]. Pocard’s data from St. Antoine University Hospital examined salvage APR in 21 patients who had either residual disease after sphincter conservation or recurrence [41]. The actuarial 5-year survival rate was 30%. Factors result- ing in failure were lymphadenopathy, positive margins, and distant disease.
Recent studies documenting experience with salvage APR after sphincter- sparing treatment are recorded below (Table 6.4).
Contraindications for salvage surgery include medical debilitation, known distant metastases, invasion of the pelvic sidewalls, and obvious inguinal lymphadenopathy. The preoperative assessment should include a chest X-ray and an MRI or CT scan. Imaging of the abdomen and pelvis should include fine cuts (2–3 mm) through the pelvis, to help visualize prox- imity to unresectable structures (such as the iliac arteries or the sciatic nerve). A multidisciplinary approach is appropriate when local invasion of resectable structures occurs (such as the urinary bladder, cervix, vagina, or sacrum below the S2 level). The team should include a urologist, neurosur- geon, orthopedic surgeon, and perhaps a plastic surgeon. Recurrences close to the pelvic sidewall may be indistinguishable intraoperatively from fibro- sis and scarring from prior radiation or surgery. An intraoperative frozen section may be useful if after-loading brachytherapy catheters, iodine seeds, or intraoperative radiation therapy (boost of 1740 Gy) will be used. The role and long-term outcomes of brachytherapy as an adjunct for salvage surgery has not yet been validated.
The complications of salvage pelvic surgery are often difficult, for both the patient and the surgeon. Perineal wound dehiscence and necrosis can have debilitating consequences. Tissue coverage in previously radiated fields provides a way to improve wound healing; many consider it essential in postexenteration reconstruction. Pedicle flaps are routinely taken from the gluteus, gracilis, or rectus abdominus muscles.
Table 6.4. Abdominoperineal resection (APR) after failure of radiation (with or without chemotherapy) for anal cancer.
Author Year No. Median Follow Alive 5-year Survival
of APRs Up (m) (%) Rate (%)
Zelnick et al. 1992 9 20 <10 —
Tanum 1993 9 36 67 —
Lasser 1993 14 36 50 —
Ellenhorn et al. 1994 38 47 — 44
Longo et al. 1994 11 25 18 —
Hill et al. 1996 11 25 18 —
Pocard et al. 1997 21 40 48 33
Table modified from Pocard M, Tiret E, Nugent K, Dehni N, Parc R. Results of salvage abdominoperineal resection for anal cancer after radiotherapy. Dis Colon Rectum. 1998;
41:1488–1493.
9. Chemoradiation Salvage After Local Resection
Long-term follow-up data is lacking regarding radiation or chemoradiation salvage after local excision. Patients who undergo primary excision for anal-canal carcinoma do so for a number of reasons, including polypectomy, haemorrhoidectomy, excisional biopsy, as well as local excision with intent- to-cure. It is unclear at this point whether further treatment for completely excised, early-stage lesions is appropriate. Nonetheless, patients with posi- tive margins, or with tumours harbouring vascular or lymphatic invasion with poorly differentiated characteristics, are candidates for further therapy.
A retrospective analysis from Memorial Sloan-Kettering Hospital in 1999 involved 14 patients who underwent postoperative chemoradiation (either 30 or 45–50 Gy) [42]. Actuarial 5-year local control rates were 93%, with no differences in outcome with the higher versus lower doses [42].
Longo published the largest single retrospective analysis of outcomes in 1994 documenting his experience with chemoradiation after local excision.
The overall local control rate at 5 years was 79% in 109 patients (median dose, 42 Gy). Stratification of the data by stage revealed a 90% local control rate for stage I; 54%, stage II; and 100%, stage III [34]. Current studies suggest that incompletely excised tumours, those with poor histologic characteristics, and those that are stage II and above are candidates for chemoradiation after excision. As with primary therapy, chemotherapy (principally infusional 5-FU with mitomycin-C) seems to promote effective local control at lower radiation doses [29,31,34,42].
10. Evaluation After Treatment
Close follow up is considered imperative, but the modalities and frequency are matters of debate. After multimodality therapy, it is not known exactly what time period is required before maximal tumour regression occurs.
After that time, any disease detected is residual and salvage therapy is war- ranted. Most surgeons require follow up every 2 to 3 months. Tumours regress rather slowly after treatment, so 2 to 3 months probably represents a logical initial time period [44]. Biopsy of any residual mass may reveal nonviable cancer cells and fibrosis. Because local failure is the rule in 80%
of cases that recur, some surgeons advocate interval biopsy every 3 months, but there is no consensus on the duration of this practice. An alternative strategy involves the use of ERUS inspection and physical examination. At the University of Minnesota, the current protocol is ERUS inspection every 4 months for 3 years, then every 6 months for 2 years. Suspicious tissue or lymph nodes can then be biopsied under ultrasound guidance. The presence of inguinal lymphadenopathy after excision and multimodality therapy may represent a normal response to ongoing inflammation. However, persistent or new adenopathy must be biopsied to rule out lymphatic spread.
6. Investigation and Management of Malignant Anal-Canal Tumours 129
11. Screening, Evaluation, Treatment, and Follow-Up of ASIL
Retrospective analysis of outcome for patients undergoing wide local exci- sion of HSIL has reinforced the shortcomings of this technique. Total exci- sion is difficult and recurrence frequent. Brown found that nearly one half of 19 such patients had an incomplete excision with positive margins, and that 12 of them had biopsy-proven recurrent HSIL within 1 year. No patient developed invasive cancer, but 5 had complications (ranging from anal stenosis to faecal incontinence postoperatively) [46]. Even so, when sur- veyed, most colorectal surgeons opt for wide local excision for patients with small lesions (<3 cm); 87% also use wide local excision for larger lesions.
However, 74% treat patients with microscopic disease conservatively, at widely varying follow-up intervals, but without further surgery; most patients in that category have an incidental finding of HSIL in a haemor- rhoidectomy specimen [17,47].
Prior to wide local excision, most surgeons advocate some sort of anal mapping to delineate extent of disease, for example, serial punch biopsies (with 2- to 4-mm corneal punch biopsy forceps at 1-cm intervals cir- cumferentially). The use of 5% acetic acid solution with high-resolution anoscopy is also common. The vinegar solution causes dysplastic mucosa and skin to blanch. Biopsies are then taken from this area [17].
Wide local excision presents reconstruction issues in an area that is dif- ficult to heal. Small defects can be primarily closed or left open to granu- late and then secondarily close. Large defects merit advancement flap or skin graft closure. Other techniques described to eradicate HSIL include ablative therapies (such as cautery fulguration, CO2 laser ablation, photo- dynamic therapy, and argon-beam destruction). None of these techniques yield a pathologic specimen, and none have been studied prospectively.
Some retrospective series with very small patient numbers have indicated that photodynamic therapy, in particular, may be promising, offering abla- tion without severe morbidity. However, prospective trials must first be done prior to recommending these treatments as primary therapy for HSIL [17,48,49].
Medical treatments for HSIL have not been well-validated or pro- spectively studied. Oral and topical retinoids, immune modifiers such as imiquimod and intralesional interferon, and 5-FU cream have not proven effective, although clinical trials are ongoing [13].
Palefsky’s group at the University of California, San Francisco, has the most experience with the evaluation, treatment, and follow up of a large high-risk population with ASIL, consisting of both HIV-positive and HIV- negative men. Palefsky advocates a cost-effective prevention program in high-risk populations that is very similar to cervical-cancer–screening strategies. A complete history is taken, with specific questions asked con-
cerning anal discharge, pain, or bleeding. An anal Pap smear with high- resolution anoscopy is performed, followed by a digital rectal exam and inguinal lymph node palpation. Further treatment is based on Pap smear findings (Figure 6.4) [13,50].
Unfortunately, optimal follow-up for other, lower-risk groups (such as heterosexual men and women with anal condyloma) are not defined. Pro- spective studies in these groups are much more difficult, the numbers of affected individuals are fewer, and medical follow up is less likely. Even so, a number of possibly high-risk subgroups, including women diagnosed with cervical dysplasia and prostitutes, may benefit from this algorithm as well.
References
1. Spratt JS. Cancer of the anus. J Surgical Oncol. 2000;74:173–174.
2. Rickert RR, Compton CC. Protocol for the examination of specimens from patients with carcinomas of the anus and anal canal: a basis for checklists.
Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med. 2000;124:21–25.
6. Investigation and Management of Malignant Anal-Canal Tumours 131
Figure 6.4. Protocol for screening for anal squamous intraepithelial lesions in HIV+ and HIV- homosexual men. *ASCUS is “atypical squamous cells of indeter- minate significance.” (Reprinted with permission from Palefsky JM. Anal squamous intraepithelial lesions in human immunodeficiency virus-positive men and women.
Semin Oncol. 2000;27: 476.)
3. Thompson-Fawcett MW, Mortensen NJ McC. Anal transitional zone and colum- nar cuff in restorative proctocolectomy. Br J Surg. 1996;83:1047–1055.
4. Fenger C. The anal transitional zone. Acta Pathol Microbiol Scand. 1979;87:
379–386.
5. Shun Wong C, Tsao MS, Sharma V, Chapman WB, Pintilie M, Cummings BJ.
Prognostic role of p53 protein expression in epidermoid carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 1999;45:309–314.
6. Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery of the Colon, Rectum, and Anus. St. Louis, MO: Quality Medical Publishing, Inc, 1992:412.
7. Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg. 1976;184:422–428.
8. Singh R, Nime F, Mittleman A. Malignant epithelial tumors of the anal canal.
Cancer 1981;48:411–415.
9. Greenall MJ, Quan SHQ, Stearns MW, Urmacher C, DeCosse JJ. Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results.
Am J Surg. 1985;149:95–101.
10. Stearns MW Jr, Quan SHQ. Epidermoid carcinoma of the anorectum. Surg Gynecol Obstet. 1970;131:953–957.
11. Frisch M, Olsen JH, Bautz A, Melbye M. Benign anal lesions and the risk of anal cancer. N Engl J Med. 1994;331:300–307.
12. Frisch M, Johansen C. Anal carcinoma in inflammatory bowel disease. Br J Cancer. 2000;83:89–90.
13. Palefsky JM. Anal squamous intraepithelial lesions in human immunodeficiency virus-positive men and women. Semin Oncol. 2000;27:471–479.
14. Daling JR, Weiss NS, Hislop TG, et al. Sexual practices, sexually transmitted disease, and the incidence of anal cancer. N Engl J Med. 1987;317:973–977.
15. Palefsky J, Holly EA, Hogeboom CJ, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr. 1998;17:314–319.
16. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med.
2000;342:792–800.
17. Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Perianal Bowen’s disease and anal intraepithelial neoplasia: Review of the literature. Dis Colon Rectum. 1999;42:945–951.
18. Goedert JJ. The epidemiology of acquired immunodeficiency syndrome malig- nancies. Semin Oncol. 2000;27:390–401.
19. Melbye M, Frisch M. The role of human papillomaviruses in anogenital cancers.
Semin Cancer Biol. 1998;8:307–313.
20. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH. Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol. 1999;
37:3316–3322.
21. Scholefield JH. Anal intraepithelial neoplasia. Br J Surg. 1999;86:1363–1364.
22. Moscicki A-B, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev.
1999;8:173–178.
23. Stephenson J. Health agencies update: anal cancer screening. JAMA. 2000;
283:3060.
24. Frisch M, Glimelius B, Wohlfahrt J, Adami H-O, Melbye M. Tobacco smoking as a risk factor in anal carcinoma: an antiestrogenic mechanism? J Natl Cancer Inst. 1999;91:708–715.
25. Magdeburg B, Fried M, Meyenberger C. Endoscopic ultrasonography in the diagnosis, staging and follow-up of anal carcinomas. Endoscopy 1999;31:
359–364.
26. Maier AG, Kreuzer SH, Herbst F, et al. Transrectal sonography of anal sphincter infiltration in lower rectal carcinoma. Am J Roentgenol. 2000;175:
735–739.
27. Wasvary HJ, Barkel DC, Klein SN. Is total colonic evaluation for anal cancer necessary? Am Surg. 2000;66:592–594.
28. Jass JR, Sobin LH. Histologic Typing of IntestinalTtumours: World Health Orga- nization. 2nd ed. New York, NY: Springer-Verlag; 1989:41–47.
29. Klas JV, Rothenberger DA, Wong WD, Madoff RD. Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes. Cancer 1999;85:
1686–1693.
30. Staib L, Gottwald T, Lehnert T, et al. Sphincter-saving treatment in epidermoid anal cancer: cooperative analysis of 142 patients in five German university sur- gical centers. Int J Colorectal Dis. 2000;15:282–290.
31. Rich TA. Infusional chemoradiation of rectal and anal cancer. Oncology 1999;
13:131–134.
32. Cummings BJ. The role of radiation therapy with 5-fluorouracil in anal canal cancer. Semin Radiat Oncol. 1997;7:306–312.
33. Corman ML, Haggitt RC. Carcinoma of the anal canal. Surg Gynecol Obstet.
1977;145:674.
34. Longo WE, Vernova AM, Wad TP. Recurrent squamous cell carcinoma of the anal canal: predicators of initial treatment failure and results of salvage therapy.
Ann Surg. 1994;220:40–49.
35. Nigro ND, Vaitkevicuis VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17:354–356.
36. Enker WE, Heilwell M, Janov AJ. Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Arch Surg. 1986;121:1386.
37. UKCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5- fluourouracil, and mitomycin. Lancet 1996;348:1049–1054.
38. Flam M, John M, Pajak TF, et al. Role of mitomycin in combinaton with fluo- rouracil and radiotherapy, and of salvage chemoradiation in the definitive non- surgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;14:2527–2539.
39. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gas- trointestinal Cooperative Groups. J Clin Oncol. 1997;15:2040–2049.
40. Allal AS, Obradovic M, Laurencet F, et al. Treatment of anal carcinoma in the elderly: feasibility and outcome of radical radiotherapy with or without con- comitant chemotherapy. Cancer 1999;85:26–31.
6. Investigation and Management of Malignant Anal-Canal Tumours 133
41. Pocard M, Tiret E, Nugent K, Dehni N, Parc R. Results of salvage abdominoper- ineal resection for anal cancer after radiotherapy. Dis Colon Rectum.
1998;41:1488–1493.
42. Hu K, Minsky BD, Cohen AM, et al. 30 Gy may be an adequate dose in patients with anal cancer treated with excisional biopsy followed by combined- modality therapy. J Surg Oncol. 1999;70:71–77.
43. Tyring S. Immune response modification: imiquimod. Aust J Dermatol. 1998;
39:S11–S13.
44. Cummings BJ, Keane TJ, O’Sullivan B, et al. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mito- mycin-C. Int J Radiat Oncol Biol Phys. 1993;21:1115–1125.
45. Volberding P. Looking behind: time for anal cancer screening. Am J Med. 2000;
108:674–675.
46. Brown SR, Skinner P, Tidy J, Smith JH, Sharp F, Hosie KB. Outcome after sur- gical resection for high-grade anal intraepithelial neoplasia (Bowen’s disease).
Br J Surg. 1999;86:1063–1066.
47. Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Treat- ment options for perianal Bowen’s disease: survey of American Society of Colon and Rectal Surgeons members. Am Surg. 2000;68:686–688.
48. Morton CA, Whitehurst C, McColl JH, Moore JV, MacKie RM. Photodynamic therapy for large or multiple patches of Bowen disease and basal cell carcinoma.
Arch Dermatol. 2001;137:319–324.
49. Runfola MA, Weber TK, Rodriguez-Bigas MA, Dougherty TJ, Petrelli NJ.
Photodynamic therapy for residual neoplasms of the perianal skin. Dis Colon Rectum. 2000;43:499–502.
50. Goldie SJ, Kuntz KM, Weinstien MC, Freedberg KA, Welton ML, Palefsky JM.
The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA.
1999;281:1822–1829.
